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Precision Medicine With Zibotentan in Microvascular Angina (PRIZE)

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ClinicalTrials.gov Identifier: NCT04097314
Recruitment Status : Recruiting
First Posted : September 20, 2019
Last Update Posted : October 23, 2019
Sponsor:
Collaborators:
The University of Glasgow
King's College London
The University of Oxford
Oxford University Hospital NHS Foundation Trust
The University of Cambridge
Papworth Hospital NHS Foundation Trust
Blackpool Teaching Hospitals NHS Foundation Trust
Royal Free London NHS Foundation Trust
AstraZeneca UK Ltd
Siemens Healthcare Ltd
Information provided by (Responsible Party):
NHS Greater Glasgow and Clyde

Tracking Information
First Submitted Date  ICMJE July 5, 2019
First Posted Date  ICMJE September 20, 2019
Last Update Posted Date October 23, 2019
Actual Study Start Date  ICMJE October 18, 2019
Estimated Primary Completion Date April 30, 2022   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: September 19, 2019)
EFFICACY - Exercise Testing (treadmill exercise time, seconds) [ Time Frame: 34 weeks ]
The primary outcome is the treadmill exercise time (TET) measured in seconds using the Full Bruce protocol, a measure of aerobic capacity that reflects disease severity. A within-subject improvement in exercise time (tested at week 10 (baseline), week 22 (crossover) and week 34 (final visit)) of 30 seconds is considered clinically relevant.
Original Primary Outcome Measures  ICMJE Same as current
Change History
Current Secondary Outcome Measures  ICMJE
 (submitted: September 19, 2019)
  • EFFICACY - Health Status QLQ (Seattle Angina Questionnaire) [ Time Frame: 34 weeks ]
    Seattle Angina Questionnaire (SAQ) Summary Score and component scores (Angina Limitation, Angina Stability, Angina Frequency, Treatment Satisfaction and Quality of Life) will be recorded at all study visits.
  • EFFICACY - Health Status QLQ (Illness Perception - Brief IPQ) [ Time Frame: 34 weeks ]
    Brief Illness Perception Questionnaire (Brief IPQ), a nine-item scale designed to rapidly assess the cognitive and emotional representations of illness taken at all study visits.
  • EFFICACY - Health Status QLQ (Anxiety/depression - PHQ4) [ Time Frame: 34 weeks ]
    The Four-Item Patient Health Questionnaire (PHQ-4) for Anxiety and Depression is a validated tool for detecting both anxiety and depressive disorders and will administered at all study visits
  • EFFICACY - Health Status QLQ (Treatment satisfaction - TSQM) [ Time Frame: 34 weeks ]
    The 14-item Treatment Satisfaction Questionnaire for Medication (TSQM) is a reliable and valid instrument to assess patients' satisfaction with medication, providing scores on four scales - side effects, effectiveness, convenience and global satisfaction and will administered at all study visits
  • EFFICACY - Health Status QLQ (EQ5D-5L) [ Time Frame: 34 weeks ]
    The 5-item EuroQol Group EQ5D-5L is a validated questionnaire comprising mobility, self-care, usual activities, pain/discomfort and anxiety/depression to quantitatively assess patient's self-reported health status and will be administered at each study visit.
  • FEASIBILITY - Withdrawal Rate [ Time Frame: 34 weeks ]
    Participant withdrawal rate from study will be measured throughout.
  • SAFETY - SAEs [ Time Frame: 34 weeks ]
    Number of Participants With Treatment-Related Adverse Events as Assessed and reported by local study teams throughout trial.
  • EFFICACY - Exercise Testing (time,sec to 1mm ST-depression) [ Time Frame: 34 weeks ]
    Within-subject improvements in time (seconds) to 1 mm ST-depression during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
  • EFFICACY - Exercise Testing (maximum ST-segment deviation, mV) [ Time Frame: 34 weeks ]
    Within-subject improvements in maximum ST-segment deviation (mV) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
  • EFFICACY - Exercise Testing (Time (s) to 75% of max age-related heart rate during exercise) [ Time Frame: 34 weeks ]
    Within-subject improvements in time (seconds) to 75% of max age-related heart rate during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit).
  • EFFICACY - Exercise Testing (Metabolic equivalent (METs) [ Time Frame: 34 weeks ]
    Within-subject improvements in metabolic equivalent (METs) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). The resting metabolic rate is defined as 3.5 ml O2/kg/min (METs).
  • EFFICACY - Exercise Testing (DUKE Score) [ Time Frame: 34 weeks ]
    Within-subject improvements in Duke treadmill score (DTS) during exercise tolerance testing will be assessed using the Full Bruce protocol. Assessments will be during screening, week 10 (baseline), week 22 (crossover) and week 34 (final visit). Duke treadmill score is defined as maximum exercise time in minutes - (5 × the maximal net ST-segment deviation in mm during or after exercise) - (4 × the treadmill angina index (where 0 = no angina, 1 = non-limiting angina, 2 = exercise limiting angina).
Original Secondary Outcome Measures  ICMJE Same as current
Current Other Pre-specified Outcome Measures
 (submitted: September 19, 2019)
  • EFFICACY - Pharmacodynamics (Exploratory) [ Time Frame: 34 weeks ]
    Blood samples will be obtained at weeks 10, 22 and 34 to measure circulating concentrations of mechanistic biomarkers. These analyses are intended to provide insights into the mechanisms of treatment-related efficacy and safety responses.These measurements will be considered an exploratory endpoint.
  • EFFICACY - Pharmacokinetics (Exploratory) [ Time Frame: 34 weeks ]
    Blood samples will be obtained at weeks 10, 22 and 34 to measure steady-state plasma concentrations of zibotentan with a validated assay. These measurements will be considered an exploratory endpoint.
  • EFFICACY - Angina Diary (Exploratory) [ Time Frame: 34 weeks ]
    A novel, bespoke questionnaire for the diagnostic classification of patients with ischaemia with non-obstructive coronary artery disease (INOCA) and their treatment response will be assessed as an exploratory outcome. Patients are asked to complete this diary every time they suffer angina symptoms over the course of the trial.
Original Other Pre-specified Outcome Measures Same as current
 
Descriptive Information
Brief Title  ICMJE Precision Medicine With Zibotentan in Microvascular Angina
Official Title  ICMJE A Randomised, Double-blind, Placebo-controlled, Cross-over Trial of Zibotentan in Microvascular Angina
Brief Summary

Microvascular angina (MVA) is caused by abnormalities of the small vessels in the heart. Endothelin is a small chemical that circulates and accumulates in the blood vessel walls, causing them to narrow or go into spasm and thicken in the longer term especially as levels of endothelin increase. As a result, patients experience pain, psychological burden and an inability to carry out daily activities.

Originally developed by AstraZeneca for cancer treatment, prior research has confirmed that Zibotentan relaxes the small blood vessels of patients with MVA which lends support to the idea that Zibotentan may bring some benefits to patients with MVA. This trial therefore proposes to look into re-purposing zibotentan as a new treatment for patients with MVA. The primary objective is to assess the effect of add-on treatment with Zibotentan to treadmill exercise times in adult patients with MVA and impaired exercise intolerance. Zibotentan could provide a new treatment pathway for patients, as well as be made available to the NHS at substantially lower cost than the currently used medications.

The trial aims to initially invite approx. 356 participants for genetic testing. A minimum of 100 participants will go forward into the main study, receiving either 10mg zibotentan or a dummy matched tablet (placebo) daily over two 12 weeks periods of each, completing their final visit at week 34. The study assessments will involve a health check at each visit, including information on the patient's wellbeing, blood tests, some quality of life questionnaires, and an exercise test. Participants will also have the option to consent to additional sub-study cardiovascular MRI scanning. Finally, participants will be invited to provide consent for long-term follow-up (maximum 20 years) of their electronic medical records (no additional patient contact).

Detailed Description Not Provided
Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 2
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Condition  ICMJE Microvascular Angina
Intervention  ICMJE
  • Drug: Zibotentan
    10mg OD Zibotentan
  • Drug: Placebo oral tablet
    Placebo
Study Arms  ICMJE
  • Experimental: Zibotentan
    Intervention: Drug: Zibotentan
  • Placebo Comparator: Placebo
    Intervention: Drug: Placebo oral tablet
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: September 19, 2019)
356
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE November 30, 2022
Estimated Primary Completion Date April 30, 2022   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

Inclusion Criteria:

  1. Age >18 years.
  2. Microvascular angina - as defined by COVADIS diagnostic criteria for microvascular angina.
  3. Able to comply with study procedures.
  4. Written informed consent.

Exclusion Criteria:

  1. Exercise tolerance >540 seconds in men and >430 seconds in women (i.e. actual exercise duration (s) achieved on the Bruce protocol commensurate with predicted), or, lack of anginal symptoms and/or ST-segment depression (0.1 mV) limiting exercise.
  2. Non-cardiovascular exercise-limiting problem e.g. morbid (or severe) obesity (BMI ≥40.0 kg/m2)
  3. Genotype not available
  4. Women who are pregnant, breast-feeding or of child-bearing potential (WoCBP) without a negative pregnancy test and who are unwilling or unable to follow the reproductive restrictions and use highly effective contraception as defined in Appendix 3 of the protocol for the duration of the study treatment and 30 days after last dose of study drug.
  5. Men who are sexually active with a WoCBP who are unwilling to use condoms or other highly effective methods of contraception for the duration of study treatment and for 14 weeks after last dose of study drug.
  6. Heart failure (New York Heart Association Grade ≥II i.e. mild symptoms and slight limitation during ordinary activity)
  7. Recent (<3 months) myocardial infarction
  8. A history of epilepsy, other CNS adverse events, neurologic symptoms or signs consistent with spinal cord compression or CNS metastases.
  9. Moderate or more severe renal impairment (GFR < 45 mL/min)
  10. Liver disease with a Child-Pugh score of A (5-6 points) or higher
  11. Participation in another intervention study involving a drug within the past 90 days or 5 half-lives whichever is longer (co-enrolment in observational studies is permitted).
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 18 Years and older   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Colin Berry, MBChB BSc PhD +441413303325 Colin.Berry@glasgow.ac.uk
Contact: Jill Dempster, MA BSc (Hons) +441413140335 Jill.Dempster@ggc.scot.nhs.uk
Listed Location Countries  ICMJE United Kingdom
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT04097314
Other Study ID Numbers  ICMJE GN18CA068
Has Data Monitoring Committee Yes
U.S. FDA-regulated Product
Studies a U.S. FDA-regulated Drug Product: No
Studies a U.S. FDA-regulated Device Product: No
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party NHS Greater Glasgow and Clyde
Study Sponsor  ICMJE NHS Greater Glasgow and Clyde
Collaborators  ICMJE
  • The University of Glasgow
  • King's College London
  • The University of Oxford
  • Oxford University Hospital NHS Foundation Trust
  • The University of Cambridge
  • Papworth Hospital NHS Foundation Trust
  • Blackpool Teaching Hospitals NHS Foundation Trust
  • Royal Free London NHS Foundation Trust
  • AstraZeneca UK Ltd
  • Siemens Healthcare Ltd
Investigators  ICMJE Not Provided
PRS Account NHS Greater Glasgow and Clyde
Verification Date October 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP